APPLICANT'S ABSTRACT: Progressive brain damage leading to dementia is a major concern in AIDS. Furthermore, a high percentage of HIV-infected individuals consume alcohol (ethanol), often in abusive amounts. However, alcohol's effects on neurodegeneration associated with HIV appear largely unstudied. The HIV-1 coat protein, gp120, is a possible neurotoxin underlying AIDS-related brain damage. GP120 promotes glutamate (NMDA) receptor-mediated excitotoxicity, presumably via stimulating glia to release release factors (esp. Arachidonic acid) that increase extracellular glutamate. Likewise, NMDA receptors and glia are known alcohol targets. Our goal is to better understand how alcohol affects the extent, nature and mechanisms of neurotoxicity due to gp120. This will be approached in AIMS I and II with recombinant gp120 and rat brain organotypic slice cultures, and in AIM III with gp120 transgenic mice. Our overall hypothesis is that alcohol modifies brain neurodegeneration associated with gp120 in diametrically opposite directions, depending on alcohol concentrations and mode of exposure. Limited exposure to subneurotoxic alcohol concentrations may actually reduce gp120-dependent neurotoxicity; indeed, this is indicated by our preliminary in vitro experiments. Whether this effect of alcohol is due to reduced glial number, impairment of gp120's glial actions, or inhibition of MNDA receptor function will be tested. In contrast, chronic alcohol exposure may worsen CNS deficits in AIDS, and experimentally it exacerbates excitotoxicity due to MNDA or glutamate. Thus we anticipate that long-term or severe episodic alcohol exposure will increase neuronal (apoptotic) damage associated with gp120. If so, we will examine if augmentations in NMDA receptors and function, and/or brain edema (which we find to be a key factor in cytotoxicity caused by episodic alcohol alone) underlie the phenomenon. Specific Aim I is: To determine with rat brain organotypic slice cultures the outcome of alcohol exposure on the extent and type (apoptotic, necrotic) of gp120-mediated neurodegeneration; Aim II: To unravel the mechanisms through which alcohol affects the gp120 neurotoxicity in the brain slice cultures; and AIM III: To ascertain if the effects and actions of alcohol on gp120-induced neurodegeneration in vitro are reproduced in vivo in transgenic mice that express brain gp120 and show neuronal damage. The studies have the potential of providing information on alcohol/gp120 neurotoxicity that could be useful in understanding dementia in alcohol-consuming AIDS patients.